Autosome Errors

Question 1

categories of genetic disorders

Answer 1

chromosomal (cytogenetic)

syndromic (dysmorphologic)

metabolic (inborn errors of metabolism)

Question 2

nondisjunction

Answer 2

failure of 2 homologous chromosomes to separate during meiosis I

-or-

2 chromatids of a chromosome to separate during meiosis II or mitosis

RESULT: one daughter cell with 2 homologous chromosomes and the other with none

Question 3

mosaicism

Answer 3

presence of 2+ genetically different cell lines derived from a single zygote

only occurs after conception (post zygote)

but differing because of mutation or mitotic nondisjunction

Question 4

when to suspect a chromosomal abnormality

Answer 4

growth restriction

structural abnormalities, especially when more than 1

developmental delay, or mental retardation

Question 5

causes of trisomies

Answer 5

nondisjunction

• advanced maternal age = higher risk
• usually meiosis I (egg has 24 instead of 23)

translocation (most common is 14;21 Robertsonian translocation)

Question 6

risk of down syndrome at maternal age of 20-21, 35+, 40+, 49+

all chromosomal abnormalities?

Answer 6

A. 1/1667 and 1/526

B. 1/385 and 1/204

C. 1/106 and 1/65

d. 1/11 and 1/7

Question 7

recurrence risk of down syndrome

Answer 7

if child has trisomy 21…

1% until 40…then the age related risk factor kicks in

if 14;21 robertsonian….

if neither are carriers (di novo) = no significant higher chance

maternal carrier = 10-15%

paternal carrier = 3-5%

Question 8

trisomy down syndrome

Answer 8

95% of down syndrome cases

47, (XX or XY), +21 (meiotic nondisjunction)

Question 9

translocation down syndrome

Answer 9

4% of down syndrome cases

46 XY, +21, der (14;21)(q10;q10)

46 XX, + 21, der (21;21)(q10;q10)

Question 10

mosaic trisomy down syndrome

Answer 10

1-2% of down syndrome cases

46, XY / 47, XY, +21

Question 11

down syndrome abnormalities

Answer 11

hypotonia (floppy baby syndrome…low muscle tone), protruding tongue, short stature

mental retardation…can reach 2nd grade level with early education

EYE MARGINS: up-slanting palpebral fissures (lateral eye), epicanthal folds (medial eye)

HANDS: clinodactyly of the 5th finger (bent towards the 4th finger), transverse palmar crease (35%)

EYES: brushfield spots (white/gray spots on periphery of iris)

INTESTINAL: duodenal atresia

CARDIAC: atrio-ventricular canal, VSD

recurrent infections, delay in milestones due to intellectual capcity and hypotonia

can notice flat face in US before birth

Question 12

natural history of down syndrome

Answer 12

survive to 60s

major morbidity due to CHD

cannot have children

treatment = early intervention…vitamin and dietary therapy is in trials but no success

Question 13

Edwards Syndrome

Answer 13

Trisomy 18 (think E for 18)

1:10,000 births - less common than Downs

prenatal and postnatal growth defects (born ~3lbs and stay small)

HEAD:
- microcephaly, prominent occiput bone

HANDS:
- clenched

HEART (usually can see these in US)

• Congenital HD (over 90%)
• transposition of great vessels
• tetralogy of fallot
• coarctation of aorta

Question 14

Edwards natural history

Answer 14

only 10% to 1 year…very few past 1 year

Question 15

Patau Syndrome

Answer 15

trisomy 13

1:15,000

HEAD:

• holoprosencephaly, severe mental defects
• cleft lip/palate (midline defects = big characteristic)

SCALP:
- aplasia cutis = looks like some person took cigarette and burned holes in the scalp, rare, probably due to inadequate blood flow but not sure

polydactyly (postaxial) - after the 5th digit, can be any combo of feet and hands

Congenital heart defects (+80%)
- VSD, pactus ductus arteriosus, ASD

single umbilical artery

omphalocele

Question 16

Patau natural history

Answer 16

15% past 1 year

rare adult

severe mental and physical abnormalities

Question 17

autosomal monosomies

Answer 17

missing one chromosome

none survive outside the 1st trimester

unless mosaic with a normal cell line

Question 18

triploidy

Answer 18

extra set of chromosomes (23)

example of imprinting

different phenotype if extra 23 is from mother or father

Question 19

maternal triploidy

Answer 19

digyny (diploid ovum fertilized by haploid sperm)

small placenta, very growth restricted fetus

generally a normal baby

Question 20

paternal triploidy

Answer 20

dispermy, paternal nondysjunction

large hydropic placenta (incomplete mole)

lots of baby malformations

3,4 syndactyly (middle and ring fingers are fused)

macrocephaly, deformed face

Question 21

metaphase vs prometaphase chromosome analysis

Answer 21

prometaphase spread allows improved band resolution and detection of smaller deletions

Question 22

crit du chat

Answer 22

affected chromosome is 5p- (deletion)

1/50,000

cry of a cat when a newborn

failure to thrive, developmental delay, hypotonia

small face, large nose, large mouth

Question 23

incidence of chromosomal trisomes 21, 18, 13

Answer 23

21 (small size) = 1/800

18 (intermediate size) = 1/10,000

13 (large size) = 1/15,000

Question 24

Robertsonian Translocation

Answer 24

one of most common type of translocations

starts usually with a carrier (less likely to occur de novo)

14q21p translocation is the most common

others can occur with any acrocentric chromosome (13, 14, 15, 21, 22)

Question 25

acrocentric chromosome =

Answer 25

have a p arm including repeated sequences and can be translocated without significant harm

Question 26

alternate segregation (balance translocation)

Answer 26

best outcome (normal phenotype)

A. normal (46 chromosomes)

B. balanced translocation carrier - offspring will have 45 chromosomes

• chromosome 21 “upside down” on top of chromosome 14
• p arm has broken off, but doesn’t contain important processes for life

offspring will be normal

Question 27

adjacent segregation (unbalanced translocation)

Answer 27

A. translocation down syndrome - many don’t survive
- 46 chromosomes but part of 21 is on top of 14

B. monosomy 21 - first trimester miscarry

C. trisomy 14 - first trimester miscarry

D. monosomy 14 - first trimester miscarry